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Review
. 2009 Feb;37(3):661-71.
doi: 10.1093/nar/gkp041.

The why and how of DNA unlinking

Zhirong Liu  1 , Richard W Deibler, Hue Sun Chan, Lynn Zechiedrich
Affiliations
Review

The why and how of DNA unlinking

Zhirong Liu et al. Nucleic Acids Res. 2009 Feb.

Abstract

The nucleotide sequence of DNA is the repository of hereditary information. Yet, it is now clear that the DNA itself plays an active role in regulating the ability of the cell to extract its information. Basic biological processes, including control of gene transcription, faithful DNA replication and segregation, maintenance of the genome and cellular differentiation are subject to the conformational and topological properties of DNA in addition to the regulation imparted by the sequence itself. How do these DNA features manifest such striking effects and how does the cell regulate them? In this review, we describe how misregulation of DNA topology can lead to cellular dysfunction. We then address how cells prevent these topological problems. We close with a discussion on recent theoretical advances indicating that the topological problems, themselves, can provide the cues necessary for their resolution by type-2 topoisomerases.

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Figures

Figure 1.
Figure 1.
Biologically relevant topological structures of DNA. Depicted are schematics of the three topological forms of DNA that topoisomerases maintain and modulate. For simplicity, each line represents a double-stranded DNA helix, as shown by the upper left inset. As indicated by the arrow sizes, most type-2 topoisomerases shift the DNA topology equilibrium toward relaxing, unknotting and decatenating. Bacterial DNA gyrase and archaeal reverse gyrase are unique enzymes that introduce supercoils into DNA. This figure is reproduced from (3).
Figure 2.
Figure 2.
The hooked juxtaposition hypothesis. The hypothesis put forth by Buck and Zechiedrich stipulates that type-2 topoisomerases unknot and decatenate by selective segment passages at hooked juxtapositions but not at free juxtapositions. Schematized here, as an example, is the hypothesized decatenating mechanism by type-2 topoisomerases of two daughter chromosomes, one red and one blue. Shown is the perspective of the small topoisomerase and the global linkage is hard to ascertain globally. Type-2 topoisomerase (schematically represented by a green circle) catalyzes segment passage specifically at a hooked juxtaposition (top row), which is more likely to occur when the two chromosomes are linked globally. The type-2 enzyme will not act at a free juxtaposition (bottom row), which is more likely to occur when two chromosomes are not linked globally (71). Although depicted here for decatenation, this model is the same for knot-generated juxtapositions as well.
Figure 3.
Figure 3.
The juxtaposition-centric computational approach. (a) The hooked, half-hooked and free juxtapositions in the simple cubic lattice (Z3) model. The schematics in (b and c) illustrate how conformational enumeration and sampling are conducted in the juxtaposition-centric approach. The geometry of a preformed juxtaposition (tube-like drawings) remains unchanged during a simulation, while the conformational possibilities of the rest of the chain(s) (dashed curves) are either enumerated exhaustively for short chains or sampled statistically using Monte Carlo techniques for longer chains. The connectivity of the dashed curves to the preformed juxtapositions in (b) are for the studies looking at two separate chains, which consider the decatenating potentials, whereas those in (c) are for one-chain studies for the corresponding unknotting potentials. In addition to the three juxtapositions shown here, the juxtaposition-centric approach has been applied to several thousand lattice juxtapositions (84,85).
Figure 4.
Figure 4.
Effects on catenane and knot populations of segment passage at (a) hooked, (b) half-hooked and (c) free juxtapositions in the simple cubic lattice model. Chain length dependences of (d) link (catenane) reduction factor RL and (e) knot reduction factor RK were computed by determining the link and knot probabilities before and after topoisomerase-like segment passage at the given juxtaposition in configurations of two chains of equal lengths (d) and conformations of a single chain (e). Chain length n is the number of edges in the lattice polygon used to model a ring polymer. Data presented in this figure are identical to that in (84,85; see these references for further computational details).
Figure 5.
Figure 5.
Unknotting effects of strand passage at specific juxtapositions depend on chain stiffness. The plot (top) shows knot reduction factors (RK, in logarithmic scale) resulting from segment passage at the hooked, half-hooked and free juxtapositions (operations are as in Figure 4a–c) as a function of the chain stiffness parameter ε for circular chains with length n = 100. In these model chains, a 180° bond angle is favored by a factor exp(ε) over a 90° bond angle. Thus, chain stiffness increases with ε, with ε = 0 corresponding to the original model from which the results in Figure 4 were obtained. The bottom drawings are representative knotted conformations at ε-values indicated by the arrows.
Figure 6.
Figure 6.
Biological consequences of DNA knotting. Shown is knotted DNA (for simplicity, each line represents a double-stranded DNA helix) and tracking polymerases (ball) with the arrows indicating the direction of force on the DNA. (a) A knot in a loose conformation. (b) A knot pulled in a tighter conformation by polymerases (blue) tracking along the DNA.
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